Targeting the LKB1-AMPK Signaling Pathway in Malignant Melanoma

BRAF kinase is a major oncogenic driver and therapeutic target in malignant melanoma. Recently, the BRAF kinase inhibitor PLX4032 (also known as RG7204) has shown remarkable anti-tumor activity in melanoma clinical trials. However, around 30% of patients developed keratoacanthomas-type squamous cell carcinomas (SCC). In addition, most of the patients developed drug resistance during the course of treatment. We have recently discovered a novel bi-directional crosstalk between BRAF and the tumor suppressor LKB1-AMPK pathway, an important signaling pathway involved in the regulation of cancer cell growth and proliferation. Based on our findings, we hypothesize that combinatorial targeting both pathways is a more effective approach to treat malignant melanoma and holds the potential to overcome current limitations associated with BRAF inhibitors. Preclinical studies have suggested that activating the LKB1-AMPK pathway is a promising strategy for cancer therapeutics. Metformin, an activator of the LKB1-AMPK pathway, is currently being used for treating type II diabetes and potentially can be adapted for cancer treatment. The goal of this proposal is to assess the therapeutic benefit of using AMPK activators (such as metformin and its analog phenformin), in combination with the BRAF inhibitors in melanoma treatment. We will evaluate the combinatory effect of AMPK activators and BRAF inhibitors on inhibiting tumor growth in preclinical mouse models. Moreover, we will investigate the potential of AMPK activators on preventing the development of BRAF inhibitor-induced SCC and the emergence of resistance to BRAF inhibitors. Our studies will provide important rational basis to develop better targeted therapy of malignant melanoma.